ABSTRACT: Immunogenicity and Vector Development Core?Core 1 The overall goal of our MTCT HIVRAD Program is to develop and evaluate maternal and infant vaccination regimens capable of preventing mother-to-child-transmission (MTCT) of HIV-1. To help achieve this goal, we propose to create an Immunogenicity and Vector Development Core (Core 1). Core 1 will support mother and infant immunogenicity studies in the Program?s two Projects and three Cores by providing vaccine immunogens (recombinant HIV-1 1086.C gp120 Envelope (Env)) (Aim 1) and modified vaccinia Ankara (MVA) vectors expressing HIV-1 1086.C Env, SIV gag, and SIV pol (Aim 2). In addition, a major emphasis of Core 1 will be to conduct studies to optimize vaccine regimens that also improve safety for use in pregnant women and infants. For these studies, optimization of vaccine regimens will be informed by immunogenicity studies in rabbit models (Aim 3). One example of such work is Core 1?s development of a HIV-1 1086.C Env and SIV gag/pol expressing, modified MVA vector that is incapable of replication in vivo in humans (Aim 2). This effort will address concerns that MVA vectors are capable of replication in some mammalian cell types, an issue that is particularly concerning in pregnancy and developing infants. In addition, adjuvants that are safe for use in pregnancy and infants have been selected and will be used to optimize systemic (IM) and mucosal (IN) HIV-1 Env immunization. For example, squalene-base emulsion adjuvants like MF59 are expected to be both safe and superior to alum, but are not approved by the FDA, Core 1 will employ rabbit models to compare the immunogenicity of HIV-1 1086.C Env adjuvanted with an MF59-like adjuvant or the FDA-approved adjuvant alum (Aim 3). This study would determine if alum is as effective as MF59-like adjuvants. If alum is as effective as MF59-like adjuvants, the results would support the use of an adjuvant that is already FDA approved. If alum is not as effective as MF59-like adjuvants (as expected), the results would provide a pre-clinical foundation for gaining FDA approval of MF59-like adjuvants. Second, because there are no FDA-approved adjuvants for nasal delivery, Core 1 will optimize intranasal immunization with recombinant HIV-1 1086.C for induction of antibody responses in breast milk and in the infant GI tract without the use of added adjuvant (Aim 3) .Taken together, successful completion of Core 1?s Aims will provide essential support for the MTCT HIVRAD Program by providing novel vaccine vectors and vaccine formulations that are safe and effective in mothers and infants that could help lead to prevention of MTCT of HIV-1.